- BioRxiv Biochemistry
- BioRxiv Bioinformatics
- BioRxiv Biophysics
- BioRxiv Cancer Biology
- BioRxiv Pharmacology and Toxicology
- BioRxiv Systems Biology
- BioRxiv Zoology
- by Lee, J., Peppi, M., Guidry, M., Fernandez, K., Chowdhury, A., Wang, L., Cunningham, L. L.Cisplatin is a widely used and effective anticancer drug. However, it causes permanent sensorineural hearing loss in over 50% of treated patients. There are no FDA-approved therapies to prevent cisplatin-induced hearing loss (CIHL) in adults, highlighting a critical unmet clinical need. Previous studies suggest that statins, commonly prescribed cholesterol-lowering drugs, are associated with reduced incidence and severity of cisplatin-induced hearing loss. Statins are primarily used to lower cholesterol, but they also exert several pleiotropic effects, making the mechanism(s) underlying this […]
- by Mazumder, A., Cooper, J., Goksal, C., Khanduja, J. S., Joh, R. I., Groos, J. J., Brockhausen, R. Y., Kanoh, J., Motamedi, M., Finkelstein, I. J., Al-Sady, B., Braun, S. J.Subtelomeres are imperfect repeats adjacent to telomeres that are repressed by heterochromatin. Although essential for genome integrity, their repetitive nature has thwarted dissection of local heterochromatin assembly and maintenance mechanisms. Here, we engineered Schizosaccharomyces pombe strains carrying fluorescent reporters at a single subtelomere. We find that subtelomeric heterochromatin is organized into discrete subdomains that nucleate at telomere-proximal and cryptic internal sites. Telomere-proximal regions depend on canonical shelterin or RNA interference nucleation pathways, while telomere-distal regions require nucleosome remodelers, histone chaperones, […]
- by Volle, R.Coinfections between respiratory viruses are frequent but their outcomes are poorly understood. Rhinoviruses (RVs) and SARS-CoV-2 are two clinically relevant respiratory pathogens circulating year-round. We used differentiated human bronchial air-liquid interface (ALI) tissue cultures to study coinfections and staggered superinfections between SARS-CoV-2 BA.2 and two RVs (RV-A1, RV-A16). RV-A16 exerted strong and sustained interference on SARS-CoV-2 replication, whereas RV-A1 showed transient effects. SARS-CoV-2 had limited impact on RVs but persisted long-term despite interference. Superinfection demonstrated that pre-established infection with either […]
- by Won, K.-J., Jin, P.-R., Davis, L., Orjala, J., Armstrong, A. T., Wang, W.-H., Kothandaraman, H., Utturkar, S. M., Bae, D., Jeong, B.-S., Wu, C., Murray, I. A., Perdew, G. H., Xiang, C., Li, J., Lee, H., Jeong, H.Fusobacterium nucleatum (Fn) is prevalently enriched in colorectal cancer (CRC), promoting CRC progression. However, Fn-derived small molecules and their host target pathways in CRC remain largely underexplored. Here, we identify that Fn produces previously unrecognized three indole-containing metabolites, fusotrisindoline (FTIN), streptindole (STIN), and trisindoline (TIN). Using AHR reporter, CYP1A1 mRNA induction, CYP1A enzyme assay, photoaffinity AHR-ligand competition, and in silico docking, we establish that these metabolites are bona fide agonists of the aryl hydrocarbon receptor (AHR), with FTIN being the […]
- by Taechowisan, T.Endophytic actinomycetes are bacteria that live inside plant tissues without causing harm to the plant, producing various bioactive compounds. This study aimed to isolate and characterize an endophytic actinomycete from Alpinia galanga roots, and to investigate its bioactive compounds. A Streptomyces strain designated AL036 was isolated and identified as Streptomyces parvulus through morphological, biochemical, and 16S rDNA sequence analysis. Similar to Streptomyces parvulus Tc022, this strain exhibited actinomycin D as its major bioactive compound. Media optimization experiments and cytotoxic activity […]
- by Dutta, C., Dutta, D., Sukla, S., Biswas, S.Dengue virus (DV) NS1, a secreted virotoxin and key pathogenic factor, can trigger immune responses with poorly understood long-term effects. This study assessed immunopathology in mice administered with DV NS1 plasmid DNA via intraperitoneal (IP), intramuscular (IM), or intravenous (IV) route for DV serotypes 1, 2, 3 & 4. IP delivery caused the most pronounced effects, including elevated AST/ALT and GRP78 levels, hyperglycemia, and altered organ weights, with DV4 NS1 showing the strongest hepatic damage. Despite serum NS1 antigen being […]
- by Dannfald, A., Cadoudal, A., Carpentier, M.-C., Merret, R., Rigal, Q., Vialaret, J., Attina, A., Kindermans, J., Berrissou, C., Koprivova, A., David, A., Hirtz, C., Favory, J.-J., Kopriva, S., Drouard, L., Deragon, J.-M.The uridine at position 34 of tRNA anticodon loops is always modified at variable levels depending on environmental conditions, but a function for this highly conserved modification has not been firmly established. Using Arabidopsis thaliana, we show that the thiolation of U34 is a prerequisite for the subsequent modifications at position 32 and 37 of the tRNALys(UUU) anticodon loop, revealing a novel modification network. Surprisingly, the level of tRNALys(UUU) is strongly increased rather than reduced in the ctu1 or ctu2 […]
- by Miyazaki, R., Aibara, K., Isse, H., Kashiwai, F., Takahashi, M., Onodera, A., Tsunekawa, Y., Yamauchi, Y., Yoshimi, K., Mashimo, T., Komiya, K., Okada, T.MicroRNAs (miRNAs) serve critical regulatory roles in gene expression and are valuable biomarkers for early disease detection. However, their inherent low concentration in biological fluids poses significant detection challenges. Although traditional methods like real-time quantitative PCR (RT-qPCR) are highly sensitive, they require thermal cycling, limiting their application in point-of-care testing (POCT). Here, we present an isothermal amplification-based miRNA detection system integrating Three-Way Junction (TWJ) formation, Multistep Low-Temperature Amplification (L-TEAM), and CRISPR-Cas3-mediated signal amplification. The integration of the Multistep L-TEAM with […]
- by Poirier, S., Rondeau-Leclaire, J., Faticov, M., Roy, A., Lajeunesse, G., Lucier, J.-F., Tardif, S., Kembel, S. W., Ziter, C., Laprise, C., Paquette, A., Girard, C., Laforest-Lapointe, I.Urban vegetation varies with socio-economic gradients, as lower-income neighborhoods often host sparser and less diverse green spaces. This disparity may affect respiratory health by influencing exposure to bioaerosols. Understanding the characteristics of this aerobiome could help anticipate risks related to allergies and other respiratory conditions. Here, we hypothesized that urban vegetation cover and socio-economic status shape urban bioaerosols. We sampled bioaerosols at 65 sites across three Canadian cities of varying population size and density using an active air sampler over […]
- by Mori, Y., Robin, P., Briggs, A. B., Levic, D. S., Wang, J., Heikes, K. L., Bagnat, M., Hannezo, E., Munjal, A.Organ development requires integration of mechanical forces, biochemical signals, and transcriptional programs to achieve proper size and architecture. Mechanotransduction feedback loops convert mechanical forces into gene-expression changes that, in turn, regulate cell behaviors such as growth and extracellular matrix (ECM) production. How these loops are coupled to developmental programs to ensure robust morphogenetic outcomes remains poorly understood. Here, we show that Yap-dependent mechanotransduction establishes a self-limiting positive feedback loop that drives the successful formation of semicircular canals in zebrafish. These […]
- by Shendure, J., Hamazaki, N., Liu, Z., Qiu, C., Kubo, C. A., Xu, S., Daza, R. M., Nichols, E., Yang, W., Vo, A., O'Neill, M. B., Lee, C.Human gastruloids are a powerful class of stem cell derived models that recapitulate key features of early embryonic development, including symmetry breaking and the emergence of three germ layers. However, they lack anterior embryonic structures and coordinated axial organization. To address this limitation, we pre-patterned human pluripotent stem cells (hPSCs) by exposing them to either anterior (FGF2) or posterior (CHIR99021 [CHIR] & retinoic acid [RA]) cues. Upon mixing, these dual-patterned hPSCs interacted and self-organized into elongated structures with both anterior […]
- by Leventhal, L., Ruffley, M. R., Carnegie Field Consortium,, Exposito-Alonso, M.As climate change intensifies, the genetic diversity and composition of natural populations will become critical for adaptation and survival. Standing genetic diversity within populations differs across a species' range, due to past demographic and natural selection processes driving the accumulation of adaptive, neutral, and deleterious variation. While accumulating genomic knowledge could be used to evaluate population extinction risk from local mal-adaptive genetic makeups, testing such approaches in natural environments remains challenging. Leveraging the genomic resources of Arabidopsis thaliana, we created […]
- by Hnizda, A., Martinez-Delgado, B., Sanchez-Ponce, D., Alonso, J., Amiel, J., Attie-Bitach, T., Bada-Navarro, A., Baladron, B., Bermejo-Sanchez, E., Brinsa, V., Bukova, I., Cazorla-Calleja, R., Cervenkova, S., Chow, S., Dusek, P., Fernandez-Prieto, M., Ghosh, S., Gomez-Mariano, G., Gregorova, A., Hamilton, M. J., Hartmannova, H., Hernandez-San Miguel, E., Herrero-Matesanz, M., Hodanova, K., Kadek, A., Kerkhof, J., Kleefstra, T., Lacombe, D., Levy, M. A., Lopez-Martin, E., Lyse, R., Man, P., Marin-Reina, P., Macnamara, E. F., McConkey, H., Melenovska, P., Mielu, L. M., Moore, D., Mrazova, L., MusEHMT1 and EHMT2 genes encode human euchromatin histone lysine methyltransferase 1 and 2 (EHMT1 alias GLP; EHMT2 alias G9a) that form heteromeric GLP/G9a complexes with essential roles in epigenetic regulation of gene expression. While EHMT1 haploinsufficiency was established as the cause of Kleefstra syndrome twenty years ago, the pathogenesis of G9a dysfunction in human disease remains largely unknown. Here, we report clinical and molecular correlates of six de novo EHMT2 variants in patients with clinical presentation, episignatures, histone modifications, and […]
- by Pillai, M., Amaral, L. A. N.Transcription factors (TF) regulate gene expression in cells by binding to specific DNA sequences. However, previous studies indicate that TF binding is a necessary but not sufficient condition for regulating gene expression. While recent advances in sequencing technologies such as Chromatin Immunoprecipitation sequencing (ChIP-seq) enable researchers to identify binding sequences at single nucleotide resolution, they often fail to distinguish between biologically relevant and non-relevant – i.e., spurious – binding events. Reliably distinguishing between these two types of binding is essential […]
- by Mizeret, R., Tollenaere, A., Deluz, C., Suter, D. M.The control of transcription factor (TF) concentrations is crucial for the precise regulation of gene expression and cell fate decisions during development. Yet, TF concentrations can display substantial temporal fluctuations and intercellular variations. How TF levels quantitatively shape genome-wide occupancy patterns remains largely unexplored. Here, we systematically investigate how physiological fluctuations in the concentrations of the pluripotency TFs OCT4, SOX2, and NANOG impact their genomic binding profiles in mouse embryonic stem cells. We uncover distinct concentration-dependent binding behaviors for each […]
- by Buckley, L., Kingsolver, J.The extent of contemporary evolution, which is mediated by interactions with plasticity, will be an important determinant of biological responses to climate change. We synthesize two functional resurvey projects that, coupled with mechanistic models, evaluate the interplay of plasticity and evolution of Pierid butterfly larval (thermal sensitivity of feeding) and adult (wing melanization) traits over recent decades. We characterize thermal environments over the resurvey periods, which we interface with developmental and (historical, current, and hypothetical) thermal sensitivity traits to examine […]
- by Aitken, S. M., Arnold, P. A., Broohouse, M. T., Cook, A. M., Danzey, L. M., Harris, R. J., Leigh, A., Nicotra, A. B.Warming and drying climate trends are driving tree dieback worldwide with broad-reaching impacts on ecosystem services. Studying decline is unavoidably a retrospective exercise in which researchers are challenged to determine whether trait values that are associated with dieback are drivers versus consquences of decline. In this study, we use the subalpine snow gum (Eucalyptus pauciflora, ssp niphophila) as a case study to illustrate how to identify whether plant traits may explain vulnerability of individual trees, assess how progression of dieback […]
- Active Site Heterogeneity Drives Differential Sialic Acid Metabolism in Enterobacteriaceae Pathogensby Vemuri, S. R., Kolla, H. B., Kurucherlapati, S., Reddy, P. N.Enterobacteriaceae pathogens like E. coli, Shigella and Salmonella are mainly associated with the food poisoning and various mucosa associated infections. These pathogens invade the host and rely on the host derived nutrients for their survival. One such nutrient is sialic acid (N-acetylneuraminic acid is the common one) which is present in the mucosal linings throughout the body. Ability of these pathogens to breakdown and utilize sialic acid for their growth is a crucial factor for their survival and pathogenesis. However, […]
- by Dimitrievikj, A., Wells, J.Chemical language models have recently become a powerful tool for the de novo generation of drug-like molecules represented as SMILES strings. A central challenge is steering generation toward compounds with favorable properties such as solubility and absorption. To this end, we investigate inference time control of generative chemical language models using activation steering. Using contrastive activation addition, we seek to improve three relevant properties: molecular size, aqueous solubility (log S), and lipophilicity (log P) without changing the model weights. We […]
- by Alyahyay, M., Dumontier, D., Djama, D. S., Jackson, M., Lugtum, A., Menezes, E. C., Ye, H., Qian, J. C., Sansone, G., Soheib, M., Mirow, A. M. C., Ibrahim, L. A., Pouchelon, G.Layer 1 of the cortex is a critical site for integrating top-down inputs onto the distal dendrites of pyramidal neurons, where inhibitory neurons modulate these inputs to enable context-dependent sensory processing. Yet, it remains unclear how behavioral context dynamically regulates inhibition in Layer 1. We discover a circuit motif in which NDNF cortical interneurons (cINs) presynaptically inhibit the axonal outputs of somatostatin (SST) cINs in Layer 1 of the visual cortex. Using combinatorial genetics, monosynaptic retrograde tracing, super-resolution imaging, optogenetics, […]